Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same

1. A method of administering prasugrel and its pharmaceutically acceptable salts to a subject suffering from an acute coronary syndrome, comprising:

identifying a subject suffering from an acute coronary syndrome;

administering to the subject a loading dose of a pharmaceutical composition comprising:

prasugrel, and

a cyclodextrin derivative of formula I:

wherein:

n is 4, 5 or 6, and

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from: —OH, a straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group, an optionally substituted straight-chain, branched, or cyclic —O—(C 1 -C 10 ) group, an optionally substituted straight-chain, branched, or cyclic —S—(C 1 -C 10 ) group, and a saccharide, and

wherein the cyclodextrin derivative is present in a concentration of at least 100:1 by weight relative to the prasugrel; and

subsequently administering to the subject a maintenance dose of said pharmaceutical composition, wherein the maintenance dose comprises a lower amount of prasugrel than the loading dose.

2. The method of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is a —O-(hydroxy-substituted-C 3 ) group.

3. The method of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently a straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group having an average degree of substitution of about 4 to about 8 per cyclodextrin derivative, and the remaining substituents are —OH.

4. The method of claim 3 , wherein the straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group is sulfobutyl ether.

5. The method of claim 3 , wherein the average degree of substitution is about 6 to about 8.

6. The method of claim 3 , wherein the average degree of substitution is about 6.5 to about 7.5.

7. The method of claim 3 , wherein the cyclodextrin derivative is a compound of formula II:

wherein R is selected from (H) 21-x or (—(CH.sub. 2 ).sub. 4 -SO 3 − Na + ) x .

8. The method of claim 7 , wherein x is 6.0 to 7.1.

9. The method of claim 3 , wherein the loading dose is administered parenterally.

10. The method of claim 9 , wherein the loading dose is administered intravenously.

11. The method of claim 10 , wherein the loading dose is administered by a bolus injection.

12. The method of claim 3 , wherein the maintenance dose is administered parenterally.

13. The method of claim 3 , wherein the maintenance dose is administered orally.

14. The method of claim 3 , wherein the loading dose comprises from about 20 mg to about 120 mg of prasugrel.

15. The method of claim 3 , wherein the loading dose comprises from about 20 mg to about 80 mg of prasugrel.

16. The method of claim 3 , wherein the loading dose comprises about 60 mg of prasugrel.

17. The method of claim 3 , wherein the maintenance dose comprises from about 1 mg to about 20 mg prasugrel.

18. The method of claim 3 , wherein the maintenance dose comprises from about 1 mg to about 10 mg prasugrel.

19. The method of claim 3 , wherein the maintenance dose comprises about 10 mg prasugrel.

20. The method of claim 3 , wherein the maintenance dose comprises about 5 mg prasugrel.

21. The method of claim 3 , wherein the maintenance dose is administered once daily.

22. The method of claim 3 , wherein the maintenance dose is administered twice daily.

23. The method of claim 3 , further comprising administering a nonsteroidal anti-inflammatory drug.

24. The method of claim 23 , wherein the nonsteroidal anti-inflammatory drug is aspirin.

25. A method for inhibiting platelet activation in a patient for which oral administration of prasugrel is contra-indicated, comprising parenterally administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising:

prasugrel, and

a cyclodextrin derivative of formula I:

wherein:

n is 4, 5 or 6, and

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from: —OH, a straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group, an optionally substituted straight-chain, branched, or cyclic —O—(C 1 -C 10 ) group, an optionally substituted straight-chain, branched, or cyclic —S—(C 1 -C 10 ) group, and a saccharide, and

wherein the cyclodextrin derivative is present in a concentration of at least 100:1 by weight relative to the prasugrel.

26. The method of claim 25 , further comprising administering a second therapeutic agent.

27. The method of claim 26 , wherein the second therapeutic agent is selected from streptokinase, alteplase, reteplase, urokinase, tenecteplase, aspirin, bivalirudin, heparin, warfarin, eptifibatide, abciximab, and tirofiban.

28. The method of claim 25 , wherein the composition is administered intravenously.

29. The method of claim 28 , wherein the composition is administered in a bolus dose.

30. A method of inhibiting platelet activation in a patient in need thereof, comprising, prior to the patient undergoing an invasive procedure, administering to the patient a therapeutically effective amount of prasugrel in a pharmaceutical composition comprising:

prasugrel, and

a cyclodextrin derivative of formula I:

wherein:

n is 4, 5 or 6, and

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from: —OH, a straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group, an optionally substituted straight-chain, branched, or cyclic —O—(C 1 -C 10 ) group, an optionally substituted straight-chain, branched, or cyclic —S—(C 1 -C 10 ) group, and a saccharide, and

wherein the cyclodextrin derivative is present in a concentration of at least 100:1 by weight relative to the prasugrel.

31. The method of claim 30 , further comprising administering a second therapeutic agent.

32. The method of claim 31 , wherein the second therapeutic agent is selected from streptokinase, alteplase, reteplase, urokinase, tenecteplase, aspirin, bivalirudin, heparin, warfarin, eptifibatide, abciximab, and tirofiban.

33. The method of claim 30 , wherein the composition is administered intravenously.

34. The method of claim 33 , wherein the composition is administered in a bolus dose.

35. A method of preparing a prasugrel composition for parenteral administration, comprising reconstituting a solid prasugrel composition with a pharmaceutically acceptable diluent, wherein the prasugrel composition comprises:

prasugrel or its pharmaceutically acceptable salt, and

a cyclodextrin derivative of formula I:

wherein:

n is 4, 5 or 6, and

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from: —OH, a straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group, an optionally substituted straight-chain, branched, or cyclic —O—(C 1 -C 10 ) group, an optionally substituted straight-chain, branched, or cyclic —S—(C 1 -C 10 ) group, and a saccharide, and

wherein the cyclodextrin derivative is present in a concentration of at least 100:1 by weight relative to the prasugrel.

36. The method of claim 35 , wherein the pharmaceutically acceptable diluent is sterile water.

37. The method of claim 35 , comprising reconstituting the prasugrel composition using from about 10 ml to about 500 ml of the pharmaceutically acceptable diluent.

38. The method of claim 35 , further comprising diluting the reconstituted solution.